In general, 5-HT4 receptor agonists are found to be useful for the treatment of a variety of diseases such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease (AD), cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, and apnea syndrome (See NPL 1; NPL 2; NPL 3; NPL 4; NPL 5; NPL 6; and NPL 7).
Alzheimer's disease is the most prevalent form of dementia. Its diagnosis is described in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., published by the American Psychiatric Association (DSM-IV). It is a neurodegenerative disorder, clinically characterized by progressive loss of memory and general cognitive function, and pathologically characterized by the deposition of extracellular proteinaceous plaques in the cortical and associative brain regions of sufferers. In the past, cholinergic hypothesis, Abeta hypothesis and tau hypothesis has been advocated and tremendous amount of researches are undertaken in each story to identify the causative mechanisms of AD.
Over the 20 years since the origins of the cholinergic hypothesis, data from numerous studies have challenged its veracity as an explanation for the syndrome of dementia in Alzheimer's disease (NPL 8). These studies, together with the emerging role of acetylcholine (ACh) in learning and memory, led to the “cholinergic hypothesis of Alzheimer's disease”. Thus it was proposed that degeneration of cholinergic neurons in the basal forebrain and the associated loss of cholinergic neurotransmission in the cerebral cortex and other areas contributed significantly to the deterioration in cognitive function seen in patients with AD. Based on this mechanism of action, acetylcholine esterase inhibitors which suppress the degradation of acetylcholine in brain synapses are in the market as the therapeutic medicines for AD.
Abeta is formed from amyloid precursor protein (APP) via separate intracellular proteolytic events involving the enzymes beta-secretase and gamma-secretase. Variability in the site of the proteolysis mediated by gamma-secretase results in Abeta of varying chain length, e.g. Abeta(1-38), Abeta(1-40) and Abeta(1-42). After secretion into the extracellular medium, Abeta forms initially-soluble aggregates which are widely believed to be the key neurotoxic agents in AD (see NPL 9), and which ultimately result in the insoluble deposits and dense neuritic plaques which are the pathological characteristics of AD (NPL 10). Several candidates of AD therapeutics based on this hypothesis, are presently in the clinical trials and some efficacy in AD patients were reported (NPL 11, NPL 12).
Above two mechanisms, 1) the induction of acetylcholine levels in the brain, and 2) the suppression of Abeta production following deposition of amyloid plaques in the cortical and associative brain regions are the promising mechanisms for AD therapy proofed in human. The mechanism 1) is exemplified by acetylcholine esterase inhibitors such as donepezil, galantamine, and rivastigmine, in the market, and the mechanism 2) is exemplified by the drugs such as Abeta antibody and secretase inhibitors, and their efficacy has been reported in clinical studies of AD.
These two mechanisms are expected to show different efficacy on the AD therapy. The mechanism 1) restores the memory and cognitive functions in patients while it is a symptomatic therapy. In the other hand, the mechanism 2) by the suppression of Abeta production should have neuro-protective function which brings a disease-modifying therapy in AD patients. Therefore, a medicine which has both mechanisms of action will be an attractive medicine for AD therapy. As far as we know, this invention is the first example of the compound which has been demonstrated both mechanisms 1) and 2) clearly in animals.
Particularly in AD, it is discussed in the literatures that 5-HT4 agonism provides both the proposed mechanisms of treatment mentioned above. Then some 5-HT4 agonists have been synthesized and the non-clinical and clinical studies have been commenced by using the agonists. However, no effective working examples in animal Abeta reducing study have been identified. For example, PRX-03140, which is developed in clinical stage, has showed Abeta reducing tendency while those efficacies were not significant suppressions in animal models (NPL 13). RS67333 has been tested for the inhibition of Abeta secretion using cell culture but has not been tested in animals (NPL 14). Therefore, this invention is the first example of the compound which has been demonstrated both above two mechanisms clearly in animals.